DE60108376T3 - METHOD FOR PRODUCING A BLISTER PACK FOR TOPIRAMATE TABLETS - Google Patents

Abstract

The present invention provides a blister package for topiramate tablets comprising a pan sheet having preformed cavities containing topiramate tablets dried to a free water content of between about 0.4% to about 1.4% and a cover sheet sealed to the pan sheet. The present invention further provides a process for blister packaging dried topiramate tablets into a blister package with improved shelf-life and stability performance. <IMAGE>

Description

Cross-reference to related applications

This application claims the priority of European Patent Application No. 00 111 229.1 , which was filed on May 25, 2000.

Technical part

The present invention provides a process for producing a blister pack containing topiramate tablets. In particular, the blister pack contains dried topiramate tablets and includes a cover sheet sealed around a nap foil.

State of the art

The pharmaceutical industry employs a variety of dosage formulations for the oral delivery of medicinal agents to patients. Typical formulations for oral administration include liquid solutions, emulsions or suspensions, as well as solid formulations such as capsules or tablets (as used herein, the term "tablet" means any shaped and compressed solid dosage form comprising caplets). Methods for the production of tablets are well known in the art, so that the drug contained therein is kept stable and effective. Accordingly, the tablet quality is measured against specifications such as appearance, hardness and drug availability, as shown by the dissolution rate and the uniformity of the content.

A variety of chlorosulfate and sulfamate esters of 2,3: 4,5-bis-O- (1-methylethylidene) -β-D-fructopyranose their anticonvulsive activity in mammals and thus their usefulness in the treatment of epilepsy are in U.S. Patent No. 4,513,006 described. In particular, the 2,3: 4,5-bis-O- (1-methylethylidene) -β-D-fructopyranose sulfamate, hereinafter referred to as "topiramate", is presently commercially available as a tablet product in starches of 25, 50, 100 and 200 mg as adjunct therapy for the treatment of adults with psychomotor seizures available (TOPAMAX ^® (topiramate) tablets). Topiramate can be prepared by following the procedures outlined in the U.S. Pat. Nos. 4,513,006 and 5,387,700 and preferably the process disclosed in Examples 1 to 3 of the U.S. Patent No. 5,387,700 is described follows. Exposure to moisture and heat, however, requires that the active ingredient of the topiramate be degraded in the solid dosage form. Degradation of topiramate tablets is readily accomplished by altering the physical appearance (discoloration of the tablet color to brown or black) and by the formation of sulfate ions, which can be readily detected by standard methods known to those skilled in the art (e.g. High pressure liquid chromatography).

To obtain tablet quality, topiramate tablets have been packaged in both high-density polyethylene (HDPE) containing a desiccant and in blister packs containing a desiccant. Stability testing over time has shown that the tablets in such packages have been preserved under various temperature, humidity and light conditions. However, the blister packages offer certain advantages over the HDPE bottles used in the currently marketed package and are therefore a preferred packaging format for topiramate tablets. Blister packs achieve the stability and commercialization characteristics of HDPE bottles, being less expensive, lighter in weight, and more convenient to store; In addition, they provide fast access, unit dosage detection and better physical protection for the product. The blister packages are particularly suitable for packaging moisture-sensitive tablets, such as topiramate, since each tablet well then becomes a primary container in direct contact with the tablet, thereby inherently trapping a minimum amount of air and associated moisture.

The tablet stability in a blister pack will therefore be a function of the physical characteristics of the materials used in the composite blister pack that affect the moisture vapor transmission and the ability to protect the enclosed product from light and moisture. Although other factors affect tablet stability, such as the moisture content of the tablets, and the packaging environment itself, manufacturers and packers have focused on improving the stability performance of the blister pack by providing wells for other materials, such as desiccants, in addition to tablet wells. For example, this describes EP 0 466 068 A a blister pack in which each tablet well with a Desiccant well is connected. In the same way describes the FR 2593152 A a blister pack in which several tablet wells are connected to a desiccant well. Since the desiccant well is as easily accessible as the tablet in the blister packs described in these references, such packaging poses a potential safety hazard FR 2660634 A a blister pack in which access to the desiccant well is reduced by the provision of another sheet which must be removed to open the desiccant well. The U.S. Patent No. 3,780,856 and 3,835,995 also describe blister packs with peelable areas that only allow access to the oral dosage form wells. Furthermore, the describes EP 0 779 872 B1 an oral dosage form well for topiramate tablets associated with a desiccant well, the desiccant well being reinforced and not easily opened. In summary, the foregoing references describe blister packs containing a desiccant and attempts to protect the user's safety by preventing access to the desiccant well.

Disclosure of the invention

An object of the invention is to provide a method for the blister packaging of dried topiramate tablets.

• (a) Trocknen einer Vielzahl von Topiramat-Tabletten bis zu einem freien Wassergehalt von zwischen 0,4% bis 1,4%, vorzugsweise zwischen etwa 0,7% bis etwa 1,2%, noch bevorzugter zwischen etwa 0,8% bis etwa 1,0%;
• (b) Plazieren der getrockneten Topiramat-Tabletten des Schritts (a) in eine Napffolie, die eine Vielzahl von Vertiefungen aufweist, wobei die Napffolie ein Metall-Kunststoff-Schichtverbund aus ortho-Polyamid/Aluminiumfolie/Polyvinylchlorid ist;
• (c) Versiegeln einer Abdeckfolie mit der Napffolie des Schritts (b), um eine Blisterverpackung zu bilden, wobei die Abdeckfolie eine einzelne Aluminiumfolienschicht ist, unter der Voraussetzung, daß die getrockneten Topiramat-Tabletten zum Zeitpunkt, an dem die Abdeckfolie mit der Napffolie versiegelt wird, einen freien Wassergehalt von weniger als 1,4% aufweisen, und wobei die Blisterverpackung kein Trockenmittel aufweist.

The present invention is directed to a method of making a blister pack containing topiramate tablets, comprising the steps of:

• (a) drying a plurality of topiramate tablets to a free water content of between 0.4% to 1.4%, preferably between about 0.7% to about 1.2%, more preferably between about 0.8% to about 1.0%;
• (b) placing the dried topiramate tablets of step (a) in a well foil having a plurality of wells, the nap foil being a metal-plastic laminate of ortho-polyamide / aluminum foil / polyvinyl chloride;
• (c) sealing a cover sheet with the nap foil of step (b) to form a blister pack, the cover sheet being a single aluminum foil layer, provided that the dried topiramate tablets are sealed at the time the cover sheet seals with the nap foil is, have a free water content of less than 1.4%, and wherein the blister pack has no desiccant.

In one embodiment of the present invention, the topiramate tablets are prepared by a process selected from the group consisting of microwave drying, vacuum drying, hot air drying, infrared drying, drying using very dry air, either static or dynamic, and drying by placing a desiccant in a storage drum with mass product for a period of time, dried.

Multiple layers are adhered to each other using techniques known to those skilled in the art.

Brief description of the drawings

1 shows the stability results over time for 100 mg and 200 mg topiramate tablets, which have different amounts of free water when stored at 40 ° C / 75% Relative Humidity (RL).

2 shows the stability results over time for 100 mg and 200 mg topiramate tablets, which have different amounts of free water, stored at 30 ° C / 60% (RL).

3 shows the rate of moisture recovery of dried 25 mg topiramate tablets under different humidity conditions.

Ways to carry out the invention

• a) die Erlangung kommerziell erhältlicher Topiramat-Tabletten;
• b) das Trocknen der Tabletten; und
• c) das Verpacken der getrockneten Topiramat-Tabletten in Blisterverpackungen ohne Trockenmittel, wie in Anspruch 1 definiert.

In general, the process for the manufacture of blister packs for topiramate tablets comprises the steps:

• a) Obtaining commercially available topiramate tablets;
• b) drying the tablets; and
• c) packaging the dried topiramate tablets in blister packs without desiccant as defined in claim 1.

The dry processes include, without limitation, microwave drying, vacuum drying, hot air drying, infrared drying, drying using very dry air, either static or dynamic, and drying by placing a desiccant in a bulk product storage drum for a period of time. As a result of using these methods to dry tablets, the temperature of the ambient air may vary over a wide range, but should not be so high as to inactivate the active ingredient.

One skilled in the art can use the dry methods of this invention to obtain the optimum tablet drying rates regardless of batch size. In particular, this invention contemplates dynamic hot air drying, increasing the inlet air volume into a tablet coating drum by 10 m ³ per kg of 850 m ³ tablets for a batch batch size of 42 kg to 2800 m ³ for a tablet batch size of 240 kg and changing the drum speed from an interval rotation to full rotation based on the tablet batch size. The term "interval rotation" refers to the process of rotating a coating drum at an average coating drum rotation speed in revolutions per minute (rpm) for less than one minute. For example, an interval rotation of "10 s / min at 10 rpm" would describe the rotation of a coating drum at a speed of 10 rpm for 10 seconds and then allow the drum to idle for 50 seconds to a standstill. In contrast to interval rotation, the term "complete rotation" refers to performing the rotation of a coating drum at a conventional coating drum rotation speed. For example, a complete rotation at "3 rpm" would describe the rotation of a coating drum at a sustained speed of 3 rpm.

The improved tablet stability and blister packaging storage time contemplated by the present invention depends on the unbound water content of the tablets, hereinafter referred to as "free water", after further drying. Since the total water content of the tablets, hereinafter referred to as "total water", as determined by the Karl Fischer titration (KF), both crystal-bound water, hereinafter referred to as "bound water" includes, and free water, the free water content by the deduction of the bound water content from the total water content. The bound water is a constant that can be calculated from the known amount of lactose in the granule formulation.

Accordingly, as shown in Table 1, topiramate tablet formulations having different amounts of lactose will have different bound amounts of water present within the tablets. The objective of the free water content contemplated by the present invention for such compositions is between 0.4% to 1.4% free water, preferably from about 0.7% to about 1.2% free water, more preferably from from about 0.8% to about 1.0% free water, and most preferably less than about 1.0% free water. Table 1 Calculation of the free water content 25 mg, 50 mg, 100 mg tablets (%) 200 mg tablets (%) Target of the clear water <1.00% <1.00% Target of the total water <2.86% <1.60% lactose monohydrate 37.00% 11.99% Calculated bound water 1.86% 0.60% Calculated free water <1.00% <1.00%

As used herein, the term "blister package" includes any type of layered package comprising a product contained between sheets of material, which sheets are adhered or sealed together by methods known to those skilled in the art; for example, below Use of an adhesive that is activated by heat and / or pressure. The sheets of material are available either as single sheets (for hand wrapping) or preferably as continuous roll-on sheets (for machine wrapping). In addition, these films are available in a variety of thicknesses.

The present invention contemplates the use of a cup and cover film having moisture vapor barrier properties that limits moisture absorption per tablet under accelerated storage conditions (40 ° C / 75% RH) to less than 0.1 mg / month.

The term "reasonable wet-steam barrier properties" is intended to encompass accepted wet-steam permeability criteria known to those skilled in the art for single unit containers and unit dosage containers for capsules and tablets. In particular, the invention contemplates the use of well and cover sheets which limit moisture absorption per tablet to less than 0.1 mg / month under accelerated storage conditions (40 ° C / 75% RH).

The "nap foil" of a blister pack designates the bottom foil of the package and is made of materials as described above. In addition, the nap foil may preformed therein contain a plurality of wells for the retention of the topiramate tablets packaged therein. During the packaging process, the wells of the napkin are molded and filled with tablets. The nap foil is then covered with an upper foil and sealed, hereinafter referred to as "cover foil". The cover sheet is made of materials as described above. In the present invention, the blister package comprises a metal and plastic composite layer OPA / Alu / PVC nap foil and a cover sheet having a single aluminum foil layer, hereinafter referred to as "Alu-Alu" blister packaging.

Alternatively, the nap foil and the cover film may each be formed independently of continuous roll film which are matched for simultaneous feeding as a mesh to a blister packaging machine.

The following specific examples are presented for the purposes of illustration and are not intended to limit the scope of the claims of the present invention.

example 1

Dry process on a test scale

Several 42 Kg tablet lots formulated in different strengths were independently loaded into a GLATT GC 750/500 (59-1 drum) coater manufactured by GLATT AG, Pratteln, Switzerland. The coater drum was rotated at 10 second per minute intervals at a speed of 10 rpm; for the remaining 50 seconds per minute, the drum was not rotated. The inflowing air was heated to about 70 ° C. The tablet dry rate was controlled by the process parameters of the coater, as by the measurement of inflow / outflow temperature and air volume. The amount of influent air was maintained at a rate of about 800 m ³ / hr to about 950 m ³ / hr, and was usually about 900 m ³ / hr to maintain a constant negative pressure in the drum. The free water content for each formulation was determined during the drying process through the use of in-process control (IPC). The IPC samples were taken every 30 min. And tested for Loss on Drying using a Mettler HR73 Halogen Dryer manufactured by Mettler-Toledo, Greifensee, Switzerland, with 5 gm samples Topiramate tablets were powdered and measured using the rapid dry setting at 105 ° C with an average weight loss that was less than about 1 mg in about 50 seconds. The drying time required for each batch of tablet to reach the target of free water content (including a period for re-heating the incoming air) varied from about 1.25 hours to about 4 hours, preferably from about 2 hours to about 3 H.

Various dry methods for the 25 mg, 50 mg, 100 mg and 200 mg tablet strengths were tested and compared. The use of microwave drying, vacuum drying and in particular drying in a hot air coating pan resulted in tablets with unaltered product quality specification, including appearance, testing procedures, degradation products and dissolution profile.

The IPC free water content results for each test scale lot dried according to the method of Example 1 are shown in Table 2. Table 2 Test scale results Strength Drying time (h) LOD start (%) ¹ LOD end (%) ² Initial KF (%) ³ initial free water (%) 25 mg 2.5 2.11 1.09 2.72 0.86 25 mg 2.25 1.74 1.26 2.74 0.88 25 mg 1.25 1.74 1.43 2.96 1.10 25 mg 3.5 1.74 1.18 2.67 0.81 50 mg 2.5 2.10 1.11 2.76 0.90 100 mg 2.5 1.98 1.09 2.66 0.80 200 mg 3 1.54 0.84 1.41 0.80 200 mg 2 1.98 1.19 1.61 1.00 200 mg 4 1.98 0.93 1.40 0.79 200 mg 3 1.98 1.07 1.48 0.87 ¹ Tested at the end of the drying process
² Initial total water (KF): after packaging in aluminum / aluminum canister
³ Initial free water calculated by deducting the water of crystallization from KF (ie 1.86% for 25 mg, 50 mg and 100 mg tablets and 0.60% for the 200 mg tablets).

Similar LOD results were obtained for production-scale tablet batches using comparable equipment to increase test batch production, as shown in Table 3. Table 3 Equipment on a production scale test scale production scale Batch size (approximately) 42 kg 240 kg SMOOTH coater GC750 / 500 GC 1350 Zuflußluftvolumen 850 m ³ 2800 m ³ Zuflußluftfeuchtigkeit not controlled 10 g / kg Zuflußlufttemperatur 70 ° C 70 ° C drum rotations 10 s / min at 10 upm 3 upm Optimum drying time 2.5 h 2.5 h

For this example, drying time for drying on a test and production scale using the method of the present invention was the same.

Example 2

Blister packaging of topiramate tablets

The topiramate tablets dried by the method of Example 1 were packaged in an aluminum / aluminum blister pack in accordance with standard operating conditions consistent with current Good Manufacturing Practices using packaging materials known to those skilled in the art:

Blisterverpackungsverfahren

• 1. The blister packaging machine tooling design 1PJ-521-030 and 1PJ-521-020 manufactured by Uhlmann Pac Systems GmbH & Co KG, Laupheim, Germany, was mounted on a Harro Höfliger type PFM65 or PFM77 blister packaging machine manufactured by Harro Höfliger Verpackungsmaschinen GmbH, Allmersbach, Germany, was used; the forming tool design has four 53 mm × 130 mm blister packs side by side per napkin, each blister pack comprising 10 individual tray wells perforated for single unit dosing.
• 2. The blister packaging nap foil was prepared from a continuous film web of OPA / Alu / PVC 25 μm / 45 μm / 60 μm film roll material manufactured by Lawson Mardon Neher AG, Kreuzlingen, Switzerland, and was set at 18 cycles per minute the Napffolienumformwerkzeug web-fed, wherein the tablet wells were cold-pressed by the dies.
• 3. The napkins were web-fed as film webs to an automatic tablet filler containing a batch of topiramate tablets which had been further dried according to the procedure of Example 1. The batch size in the tablet filling apparatus can range from about 42 kg for a batch of about 100,000 200 mg tablets on a test scale to about 240 kg for a batch size of about 3,000,000 25 mg tablets or subsets thereof on a production scale. Alternatively, the tablets may be manually filled into the preformed tablet well. The invention contemplates the use of both automatic and manual tablet filling.
• 4. The blister package cover sheet was made from a continuous 20.0 μm (54.0 g / m ² ) sheet of hard aluminum foil with a heat seal lacquer (7.0 g / m ² ) LA723 on roll stock, available from Lawson Mardon Neher AG, Kreuzlingen, Switzerland were prepared simultaneously with the Napffolienbahn web fed at 18 cycles per minute to a closure mold, which was maintained at a temperature of about 180 ° C to about 190 ° C, wherein the web-fed cover sheet welded to the web-fed Napffolie with a Verschweißdruck of 80 bar In order to thereby simultaneously form a group of four side by side welded blister packs.
• 5. The group of four sealed blister packs was then web fed to a punch, with the punch simultaneously perforating the sealed area around the filled tablet wells to form unit tray dosing units and punched into individual 10 tablet dispensing unit blister packs.

Packaging room conditions

Like in the 3 In the case of dried 25 mg topiramate tablets, the moisture recovery depends on the relative humidity of the packaging room air. In one embodiment of this invention, the humidity was maintained at less than 20% RH.

Example 3

Blisterverpackungsbewertungsstudie

• 1. DUMA HDPE-Flaschen (30, 50, 75 ml), hergestellt durch DUMA International AB, Stockholm, Schweden, die ein Trockenmittel gemäß der zugelassenen, vertriebenen Spezifikationen enthielten, die unabhängig voneinander 60 Tabletten der Stärken 25, 50, 100 oder 200 mg enthielten, wurden als Referenz verwendet;
• 2. Alu/Alu-Blisterverpackungen, die eine OPA/Alu/PVC (25 μm/45 μm/60 μm) Napffolie und einen harte Aluminiumfolienabdeckfolie (20 μm) und 10 Vertiefungen, die jeweils eine Tablette der Stärke 25, 50, 100 oder 200 mg enthielten, aufwiesen;
• 3. Blisterverpackungen, die eine PVC/PE/PVDC-Napffolie (200 µm/25 µm/90 g/m²) (unter der Plastikfilmmarke Tristar^® vertrieben) und ein harte Aluminiumfolienabdeckfolie (20 µm) und 10 Vertiefungen aufwies, wobei jede eine Tablette der Stärke 25, 50, 100 oder 200 mg enthielt, wurden in einen PE/Alu/PE (12 µm/12 µm/75 µm) Beutel mit einer darin enthaltenden Minipax^TM Trockeneinheit darin (2 g Silicagel) eingebracht, im folgenden als „Blister im Beutel”-Verpackung bezeichnet;
• 4. Blisterverpackungen, die eine PVC/PE/PVDC-Napffolie (200 µm/25 µm/90 g/m²) (unter der Plastikfilmmarke Tristar^TM vertrieben) und eine harte Aluminiumfolienabdeckfolie (20 µm) und 10 Vertiefungen aufwies, wobei jede eine Tablette der Stärke 25, 50, 100 oder 200 mg enthielt und jede mit einer von 10 Vertiefungen verbunden war, welche jede eine Trockenmitteltablette (0,5 g Silicagel) enthielt;
• 5. Blisterverpackungen, die eine PVC/PE/PVDC-Napffolie (200 µm/25 µm/90 g/m²) (unter der Plastikfilmmarke Tristar^® verkauft) und eine harte Aluminiumfolienabdeckfolie (20 µm) aufweisen, wobei jede eine Tablette der Stärke 25, 50, 100 oder 200 mg enthielt.

In view of the specification of appearance, which are defined in Table 5 below, a packaging evaluation study was carried out producing appearance data for commercially available topiramate tablets having a free water content of about 1.7, packed in various packaging formats were:

• 1. DUMA HDPE bottles (30, 50, 75 ml), manufactured by DUMA International AB, Stockholm, Sweden, which contained a desiccant according to the approved, distributed specifications, independently of each other 60 tablets of the strengths 25, 50, 100 or 200 mg were used as reference;
• 2. Alu / Alu blister packs containing an OPA / Alu / PVC (25 μm / 45 μm / 60 μm) Napffolie and a hard Aluminiumfolienabdeckfolie (20 microns) and 10 wells, each a tablet of strength 25, 50, 100 or 200 mg;
• 3. blister packs having a PVC / PE / PVDC-cupping film (200 microns / 25 microns / 90 g / m ²⁾ (under the trademark Tristar plastic film ^® sold) and a hard Aluminiumfolienabdeckfolie (20 microns) and 10 wells showed, each containing one 25, 50, 100 or 200 mg tablet were placed in a PE / Alu / PE (12 μm / 12 μm / 75 μm) bag with a Minipax ^™ drier unit contained therein (2 g silica gel), hereinafter referred to as "blister pack"packaging;
• 4. blister packs having a PVC / PE / PVDC-cupping film (200 microns / 25 microns / 90 g / m ²⁾ (under the plastic film trademark Tristar ^TM sold) and a hard Aluminiumfolienabdeckfolie (20 microns) and 10 wells showed, each having a 25, 50, 100 or 200 mg tablet, each connected to one of 10 wells, each containing a desiccant tablet (0.5 g silica gel);
• 5. blister packs having a PVC / PE / PVDC-cupping film (200 microns / 25 microns / 90 g / m ²⁾ (under the plastic film trademark Tristar ^® sold) and a hard Aluminiumfolienabdeckfolie (20 microns), with each containing a tablet of starch 25, 50, 100 or 200 mg.

The plastic film used for the previous blister was PEARLS CONVERTING AG, Perlen, Switzerland, and sold under the trade name Tristar ^® (brand plastic film). According to the flowchart shown in Table 4 below, the packages described above were placed under different conditions in stable chambers and periodically tested. (X) indicates that at times under the conditions shown in Table 4, testing was only on demand. X indicates that the appearance, active ingredient and sulfate test, purity and solubility tests were conducted at the times and under the conditions shown in Table 4. Appearance tests were performed every month for the first 7 months and X as shown in Table 4. Table 4 Blister Evaluation Study: Storage time (months) 5 ° C 25 ° C / 60% RH 30 ° C / 60% RH 40 ° C / 75% RH 0 - X - - 3 - - - - 6 - X - X 9 - X X 12 (X) X X 18 - X X 24 (X) X X 36 (X) X X 48 (X) X X

The study results for each type of packaging are shown in Table 5 below.

The study showed that the appearance of topiramate tablets with a free water content of about 1.7% for:

Packaging format 1

• 1. Continue to meet the appearance specification at room temperature (RT) at 48 months.
• 2. The appearance specification under 30 ° C / 60% RL conditions at 36 months met but missed the 48-month time point.
• 3. The appearance specification under 40 ° C / 75% RL conditions after 6 months met.

"Alu / Alu" blister packaging format 2

• 1. Passed the appearance specification at RT after 48 months.
• 2. Missed the appearance specification under 30 ° C / 60% RL conditions at 24 months (product standards require pass appearance specification after 36 months).
• 3. Failed to observe the appearance specification under 40 ° C / 75% RL conditions after 5 months (the product standards require compliance with the appearance specification at 6 months).

"Blister-in-bag" packaging format 3

• 1. Continue to achieve the Appearance Specification at RT after 48 months.
• 2. Continue to achieve the appearance specification under 30 ° C / 60% RL conditions at 48 months.
• 3. Continue to achieve the appearance specification under 40 ° C / 75% RL conditions after 36 months.

Packaging format 4

The study was discontinued after 6 months for all conditions (the packaging format was too expensive for distribution).

Packaging format 5

• 1. The study was discontinued after 12 months at RT and 30 ° C / 60% RL conditions.
• 2. Missed the appearance specification under 40 ° C / 75% RL conditions after 3 months (the product standards require compliance with the appearance specification after 6 months).

Packaging format 1 provides protection that meets the product specification, but a more pharmaceutically elegant, less expensive packaging alternative is desired. The "blister-in-a-bag" package provided better protection against humidity than the other packaging formats, but such packaging is bulky and expensive to produce on a commercial scale. The "Alu-Alu" blister pack as tested in Example 3 (ie with tablets having a free water content of about 1.7%) provided no protection that reached the product specification. However, the results of Example 4 for the "Alu-Alu" blister pack showed that by drying the tablets prior to packaging, surprisingly improved shelf life and stability of the topiramate tablets in an "Alu-Alu" blister pack is achieved. Table 5 First visible change in the tablet appearance for the Example 3 Packaging Evaluation Study format RT 30 ° C / 60% RH 40 ° C / 75% RH 1 > 48 m 36 m 6 m 2 > 48 m 24 m 5 M 3 > 48 m > 48 m 36 m 4 > 6 m > 6 m 6 m 5 > 12 m > 12 m 3 m

Appearance specification

The specifications approved for the stability of topiramate tablets are the appearance specifications shown in Table 6. The appearance of the tablet has been established as a very sensitive indicator of topiramate stability.

When the first beige spots were visible (code 2), the tablets still fulfilled all appearance conditions. However, when the amount of sulfate exceeded the specification amount of ≥ 0.5 mole%, the beige spots visibly darkened (code 3) and the tablets were assumed to fail the appearance specification. In accordance with the guidelines of the International Committee for Harmonization (ICH), the tablets must be kept within accelerated stability conditions of 40 ° C / 75% RL for at least 6 months within the approved specifications. Table 6 Physical Testing / Appearance Classification Scale specification criteria Pass / Fail Code 1 No change White fractures, no visible discoloration passed Code 2 Very slight change White break without visible discoloration and occasional yellow spots passed Code 3 Unique change Discolored breakage with dark spots Failed Code 4 Change first noticeable to the consumer Tint change on the outside of the tablet; acetone-like odor, dark fracture Failed Code 5 Extreme change Dark discoloration on the outside of the tablet Failed

Example 4

Aluminum Alloy Blisterverpackungsbewertungsstudie

• 1. Alu-Alu-Blisterverpackungen, die eine OPA/Alu/PVC-Napffolie (25 µm/45 µm/60 µm) (Verbundbogen, der durch Louis Patz & Corp., Natschbach, Österreich, hergestellt wird) und eine harte Aluminiumfolienabdeckfolie (20 µm) (das durch Tscheulin-Rothal GmbH, Teningen, Deutschland hergestellt wird) und 10 Vertiefungen aufwies, wobei jede eine Tablette von der Stärke 100 oder 200 mg enthielt, wobei jede Tablette einen freien Wassergehalt von etwa 0,8% aufwies.
• 2. Alu-Alu-Blisterverpackungen, die eine OPA/Alu/PVC-Napffolie (25 µm/45 µm/60 µm) (Verbundbogen, der durch Louis Patz & Corp., Natschbach, Österreich, hergestellt wird) und eine harte Aluminiumfolienabdeckfolie (20 µm) (das durch Tscheulin-Rothal GmbH, Teningen, Deutschland hergestellt wird) und 10 Vertiefungen aufwies, wobei jede eine Tablette von der Stärke 100 oder 200 mg enthielt, wobei jede Tablette einen freien Wassergehalt von etwa 1,4% aufwies.
• 3. Alu-Alu-Blisterverpackungen, die eine OPA/Alu/PVC-Napffolie (25 µm/45 µm/60 µm) (Verbundbogen, der durch Louis Patz & Corp., Natschbach, Österreich, hergestellt wird) und eine harte Aluminiumfolienabdeckfolie (20 µm) (das durch Tscheulin-Rothal GmbH, Teningen, Deutschland hergestellt wird) und 10 Vertiefungen aufwies, wobei jede eine Tablette von der Stärke 100 oder 200 mg enthielt, wobei jede Tablette einen freien Wassergehalt von etwa 1,8% aufwies.

With regard to the appearance specifications defined in Table 6 above, a packaging evaluation study was conducted under various stability conditions, with the appearance data for topiramate tablets having a free water content of about 0.8%, 1.4% or 1.8% that were packaged in "Alu-Alu" blister packs were produced:

• 1. Aluminum aluminum blister packs comprising an OPA / Alu / PVC nap foil (25 μm / 45 μm / 60 μm) (composite sheet manufactured by Louis Patz & Corp., Natschbach, Austria) and a hard aluminum foil cover sheet ( 20 μm) (made by Tscheulin-Rothal GmbH, Teningen, Germany) and 10 wells each containing one tablet of 100 or 200 mg, each tablet having a free water content of about 0.8%.
• 2. Alu-aluminum blister packs comprising an OPA / Alu / PVC nap foil (25 μm / 45 μm / 60 μm) (composite sheet manufactured by Louis Patz & Corp., Natschbach, Austria) and a hard aluminum foil cover foil ( 20 μm) (manufactured by Tscheulin-Rothal GmbH, Teningen, Germany) and 10 wells each containing one tablet of 100 or 200 mg, each tablet having a free water content of about 1.4%.
• 3. Alu-aluminum blister packs comprising an OPA / Alu / PVC nap foil (25 μm / 45 μm / 60 μm) (composite sheet manufactured by Louis Patz & Corp., Natschbach, Austria) and a hard aluminum foil cover sheet ( 20 μm) (manufactured by Tscheulin-Rothal GmbH, Teningen, Germany) and having 10 wells each containing one tablet of 100 or 200 mg, each tablet having a free water content of about 1.8%.

Under accelerated stability conditions of 40 ° C / 75% RL, as in 1 shown, the tablet batch with a free water content of 1.8% missed the appearance specifications listed in Table 6 after 5 months. The batch with a free water content of 1.4% missed the appearance specification after 8 months. However, the batch with a free water content of 0.8% surprisingly continues to meet the appearance specification after 12 months and failed only after 24 months.

Under stability conditions of 30 ° C / 60% RL, as in the 2 The batch with a free water content of about 1.8% did not reach the appearance specification after 24 months, however, the batches with a free water content of 0.8% free water and 1.4% free water still achieved the appearance specification after 36 months ,

As in the 1 The appearance data shown in the study showed that topiramate tablets with a free water content of about 0.8% in an aluminum / aluminum blister pack met the appearance specification for 18 months at 40 ° C / 75% RL. The study also showed that topiramate tablets with a free water content of about 0.8% to about 1.4% in an aluminum / aluminum blister pack met the appearance specification for 36 months at 30 ° C / 60% RL.

The results of the 36-month study described in Example 4 are summarized in Table 7. Table 7 Change in the tablet appearance for Example 4 water content 30 ° C / 60% RH 40 ° C / 75% RH 0.8% Passed 36th month Failed 24th month 1.4% Passed 36th month Failed 24th month 1.8% Passed 24th month Failed 24th month

The comparison of the "Alu-Alu" blister pack examined in Example 3 with the results of Example 4 shows that the tablet drying process of the present invention has surprisingly improved shelf life and stability for topiramate tablets in the "Alu-Alu". Blister packaging provides.

While the foregoing specification teaches the principles of the present invention, the examples being provided for the purpose of illustration, it will be understood that the practice of the invention includes all conventional variations, adjustments and modifications for tablet drying and blister packaging known to those skilled in the art which may come within the scope of the following claims and their equivalents.

Claims (6)

A process for making a blister pack containing topiramate tablets, comprising the steps of: (a) drying a plurality of topiramate tablets to a free water content of between 0.4% to 1.4%; (b) placing the dried topiramate tablets of step (a) in a well foil having a plurality of wells, the nap foil being a metal-plastic laminate of ortho-polyamide / aluminum foil / polyvinyl chloride; and (c) sealing a cover sheet with the nap foil of step (b) to form a blister pack, the cover sheet being a single aluminum foil layer, provided that the dried topiramate tablets are sealed at the time the cover sheet seals with the nap foil is, having a free water content of less than 1.4%, and wherein the blister pack has no desiccant. The method of claim 1, wherein the nap foil is a 25 μm ortho-polyamide / 45 μm aluminum foil / 60 μm polyvinylchloride foil and the cover foil is a 20 μm aluminum foil sheet. The method of claim 1, wherein the topiramate tablets are dried to a free water content of between about 0.7% to about 1.2%. The method of claim 3, wherein the topiramate tablets are dried to a free water content of between about 0.8% to about 1.0%. The method of claim 1, wherein the topiramate tablets are dried by a process selected from the group consisting of microwave drying, vacuum drying, hot air drying, infrared drying, drying using very dry air, either static or dynamic, and drying by placing a desiccant in a storage drum with mass product for a period of time. The method of claim 5, wherein the topiramate tablets are dried using hot air in a coater at temperatures of about 60 ° C to about 70 ° C.

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